Idiopathic pulmonary fibrosis (IPF) is a progressive, ultimately fatal form of idiopathic interstitial pneumonitis (IIP), with a 3 year survival rate of 0%. Diagnostic certainty of IPF is critical to patient management and therapeutic decision-making. Two new FDA-approved therapies, pirfenidone and nintedanib, have been shown to slow disease progression in IPF and brought new hope to IPF patients. Due to their high costs, side effects, and documented efficacy only in IPF, pulmonologists only prescribe these drugs to patients with a well- established diagnosis of IPF. Definitive IPF diagnosis can be made by chest CT alone in about half of cases when classic imaging features are present, which must include peripheral honeycombing. When CT does not visualize honeycombing, patients must undergo surgery to resect lung tissue and look for honeycombing microscopically to establish diagnostic certainty of IPF. Unfortunately, surgical lung resection has high risks of associated morbidity and mortality, including provoking further disease progression, and even death. There is a clear clinical need for a low risk method of microscopic IPF diagnosis. In this proposal, we take a hypothesis driven approach to determine whether bronchoscopic optical imaging can serve as a novel, low-risk, non- surgical paradigm for IPF diagnosis without surgery or tissue removal. Optical coherence tomography (OCT) provides rapid 3D visualization of large tissue volumes with microscopic resolutions (< 10 m, comparable with low-power microscopy) well beyond the capabilities of CT. We have developed ultrathin bronchoscopic OCT catheters and conducted in vivo peripheral lung imaging in patients. We have shown in preliminary studies that endobronchial OCT can detect microscopic honeycombing (< 1 mm diameter) in IPF that is not visible with CT. We hypothesize that minimally invasive bronchoscopic OCT can detect microscopic honeycombing and diagnose IPF with high sensitivity and specificity. In Aim 1, we will develop and validate OCT diagnostic criteria to detect microscopic honeycombing and diagnose IPF. We will create a library of airway- based OCT with matched histology from ex vivo lung specimens from patients with suspected IIP. In Aim 2, we will conduct a pilot clinical study to test the translation of bronchoscopic OCT to identify microscopic honeycombing and diagnose IPF in vivo. If successful, these studies will result in the clinical translation of bronchoscopic OCT imaging as a minimally-invasive method for IPF diagnosis, mitigating the need for surgical diagnostic procedures. This proposal addresses a significant clinical problem in a way not previously achievable, and could lead to major innovations in IPF clinical management and therapeutic decision-making. CANDIDATE Dr. Hariri is an Instructor in Pathology on the tenure track at Harvard Medical School. Her long-term career goal is to become an independent physician-scientist using optical imaging to assess pulmonary disease such as IPF. She has a strong background in optical imaging research through her graduate training as a biomedical engineer and post-doctoral research, and is one of four specialist pulmonary pathologists at MGH. Her prior research experience and clinical knowledge of IIP have optimally positioned her to conduct the proposed studies. Dr. Hariri has spent a significant portion of her research training assessing OCT for disease detection, particularly in lung cancer, in controlled preclinical and ex vivo studies. She is now ready to translate this experience to clinical optical imaging that makes direct impacts on patient care. In order to achieve her long- term career goals, she must obtain further mentoring and experience in the translation of optical imaging to the clinical setting. This proposal will provide her with this essential training, and a solid foundation on which she will build her career as an independent researcher in patient-oriented pulmonary optical imaging. MENTORING ENVIRONMENT AND TRAINING PLAN Dr. Hariri will train in an exceptional environment at MGH with abundant intellectual and collaborative opportunities, and access to all the necessary resources to conduct her research. Her mentors, Drs. Melissa Suter and Andrew Tager, are luminaries in their respective fields of clinical optical imaging and pulmonary fibrosis. Drs. Tager and Suter both have ample mentoring experience, each having mentored 15 post-doctoral trainees, of whom many have obtained K awards or full faculty positions. They have an established mentoring relationship with Dr. Hariri, and ongoing collaborations with one another. They are fully dedicated to supporting Dr. Hariri in this proposal and her transition to independence. In addition, Drs. Brett Bouma and Thomas Colby will serve on Dr. Hariri's research advisory committee and provide further respective expertise in clinical translation of optical imaging and IPF diagnosis. To complement the expertise of her mentors and the proposed research, Dr. Hariri will complete courses in biostatistics, medical imaging informatics, translational research, and clinical study design through Harvard. Through mentorship from Drs. Suter and Tager and workshops/courses held at MGH and Harvard, Dr. Hariri will gain the necessary skills to successfully transition to an independent physician-scientist, including research planning, scientific writing, applying for an R01, laboratory and budget management, responsible conduct of research, and effective mentoring.